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Purpose: To investigate how obesity affects the pharmacokinetics of biologics in a rat model., Method: Male Long-Evans rats were fed a high-fat diet from the age of 3 weeks and development of obesity was monitored by measuring body size and composition (fat and lean mass). The animals received nivolumab (1 and 8 mg/kg) or recombinant human erythropoietin (rHuEPO, 1000 IU/kg) by intravenous or subcutaneous injection. Serum samples were collected and analyzed using an enzyme-linked immunosorbent assay (ELISA). Endogenous rat IgG was also measured in the nivolumab study. A standard noncompartmental analysis was performed to calculate pharmacokinetic parameters., Results: When dosed at mg/kg of total body weight approach, no significant differences in pharmacokinetics of nivolumab and rHuEPO between lean and obese cohorts were observed despite significant differences in the body composition. Subcutaneous bioavailability of nivolumab was inversely dependent on the dose level., Conclusions: Pharmacokinetic parameters of two biologics tested in this work were not affected by obesity, and mg/kg dosing approach was necessary to achieve equivalent exposure in serum. The results were different from our previous findings of significant effect of obesity on pharmacokinetics of human IgG in rats. Additional studies with other biologics are urgently needed in preclinical and clinical settings., Competing Interests: Declarations. Conflict of Interest: None., (© 2025. The Author(s).)

Biodegradable medical devices undergo degradation following implantation, potentially leading to clinical failure. Consequently, it is necessary to assess the change in their properties post-implantation. However, a standardized method for the precise evaluation of the changes in their physicochemical properties is currently lacking. In this study, we aimed to establish precisely simulated oral physiological conditions (SOPCs) and investigate the physicochemical property changes to predict the performance alterations of biodegradable dental barrier membranes (BDBMs) following human implantation. We investigated changes in physicochemical properties of BDBM after exposure to SOPC for 24 weeks. When BDBM was exposed to SOPC for 24 weeks, there was a significant decrease in mass (-1.37%), molecular weight (-19.54%) and tensile load (-72.84%). Among the physicochemical properties, molecular weight decreased similarly after 24 weeks of implantation in rats (-15.78%) and after 24 weeks of exposure to SOPC (-19.54%). Changes in the physicochemical properties of BDBM in simulated in vitro oral conditions and in the in vivo environment were similar. Overall, the evaluation of physicochemical property changes after exposing BDBM to the proposed SOPC demonstrates novelty in its ability to accurately predict performance changes post-implantation. This approach may provide significant insights not only for the development of BDBM but also for various types of biodegradable medical devices., (Creative Commons Attribution license.)

Background: Iron is an essential micronutrient for cell survival and growth; however, excess of this metal drives ferroptosis. Although maternal iron imbalance and placental hypoxia are independent contributors to the pathogenesis of preeclampsia, a hypertensive disorder of pregnancy, the mechanisms by which their interaction impinge on maternal and placental health remain elusive., Methods: We used placentae from normotensive and preeclampsia pregnancy cohorts, human H9 embryonic stem cells differentiated into cytotrophoblast-like cells, and placenta-specific Phd2 -/- preeclamptic mice. Lipid peroxidation and iron cargo of placenta-derived small extracellular vesicles (sEVs) isolated from the maternal circulation of control and preeclampsia individuals were examined by mass spectrometry, flow cytometry, and colorimetry. Human microvascular endothelial cells' angiogenic capacity and function were examined after exposure to control and pathological sEVs., Results: Placentae from preeclampsia pregnancies contain increased ferrous iron and lipid peroxidation byproduct, malondialdehyde. Antioxidant capacity is significantly lower in preeclampsia placentae, with decreased glutathione content, and GPx4 (glutathione peroxidase 4) expression and activity. Hypoxia triggers the occurrence of ferroptosis in human trophoblast cells and mouse Phd2 - /- placentae. Disrupted placental iron homeostasis in preeclampsia is accompanied by improper extrusion of iron through sEVs mediated by the pentaspan protein prominin-2. Heightened lipid peroxidation content was found in villous explants and maternal circulating sEVs of preeclampsia individuals. Exposure of human microvascular endothelial cells to preeclampsia-derived placental sEVs results in endothelial activation and impaired angiogenesis, which is rescued by treatment with hinokitiol, a compound known to restore tissue iron balance., Conclusions: In pregnancy, iron and oxygen work synergistically to conserve an operative antioxidant system to maintain iron homeostasis and protect the placenta from ferroptotic death. Hindrance to this system due to hypoxia results in heightened ferroptosis rates and sEV-mediated extrusion of harmful lipid peroxides from trophoblast cells into the circulation thereby contributing to maternal endothelial dysfunction characterizing preeclampsia.

Objective: To propose a revised bone reporting and data system (Bone-RADS) and evaluate its diagnostic performance and inter-reader reliability compared to the original Bone-RADS for solitary bone lesions on CT., Materials and Methods: This retrospective study included 159 adult patients (mean age: 56 ± 19 years; 88 men) who underwent bone biopsy for solitary bone lesions between March 2005 and September 2021. Two radiologists (R1/2) independently categorized the lesions twice, once using the original Bone-RADS and once using the revised version. Lesions were classified as follows: (1, benign; 2, incompletely assessed; 3, indeterminate; 4, malignancy or requiring treatment). The revised Bone-RADS excluded the original criteria for lesion related pain and history of malignancy. Diagnostic performance was assessed using histopathology as the reference standard, and inter-reader reliability was analyzed., Results: The bone lesions included 96 lucent and 63 sclerotic/mixed lesions. Sensitivity showed no significant difference between the original and revised Bone-RADS for both readers across lucent and sclerotic/mixed lesions (all P ≥ .05). However, the specificity of the revised Bone-RADS was significantly higher than that of the original (lucent: 11% vs. 50% [R1], 11% vs. 46% [R2]; sclerotic/mixed: 32% vs. 92% [R1], 32% vs. 86% [R2]). Other performance metrics, including positive/negative predictive value and accuracy, were also higher in the revised Bone-RADS. Inter-reader reliability was higher for the revised Bone-RADS compared to the original (κ = .744 vs .854)., Conclusion: The revised Bone-RADS significantly improved specificity while maintaining sensitivity compared to the original version., Competing Interests: Declarations. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Consent to participate: Approval from the Institutional Review Board was obtained, and HIPAA requirements were followed. Informed consent was not required. Consent to publish: Approval from the Institutional Review Board was obtained and in accordance with retrospective review policies, informed consent was not required. Conflict of interest: The authors declare that they have no conflict of interest., (© 2025. The Author(s), under exclusive licence to International Skeletal Society (ISS).)

Natural photosynthetic systems require spatiotemporal organization to optimize photosensitized reactions and maintain overall efficiency, involving the hierarchical self-assembly of photosynthetic components and their stabilization through synergistic interactions. However, replicating this level of organization is challenging due to the difficulty in efficiently communicating supramolecular nano-assemblies with nanoparticles or biological architectures, owing to their dynamic instability. Herein, we demonstrate that the supramolecular reconstruction of self-assembled amphiphilic rhodamine B nanospheres (RN) through treatment with metal-phenolic coordination complexes results in the formation of a stable hybrid structure. This reconstructed structure enhances electron transfer efficiency, leading to improved photocatalytic performance. Due to the photoluminescence quenching property of RN and its electronic synergy with tannic acid (T) and zirconium (Z), the supramolecular complexes of hybrid nanospheres (RNT x Z y ) with Pt nanoparticles or a biological workhorse, Shewanella oneidensis MR-1, showed marked improvement in photocatalytic hydrogen production. The supramolecular hybrid particles with a metal-phenolic coordination layer showed 5.6- and 4.0-fold increases, respectively, in the productivities of hydrogen evolution catalyzed by Pt (Pt/RNT x Z y ) and MR-1 (M/RNT x Z y ), respectively. These results highlight the potential for further advancements in the structural and photochemical control of supramolecular nanomaterials for energy harvesting and bio-hybrid systems., (© 2024 Wiley-VCH GmbH.)

The rapid expansion of the cosmetics industry has significantly increased the adoption of alternative microplastics in response to increasingly stringent global environmental regulations. This study presents a comparative analysis of the treatment performance of silica powder and cornstarch-common alternatives for microplastics in cosmetics-using ceramic membrane filtration combined with flow imaging microscopy (FlowCam) to analyze particle behavior. Bench-scale crossflow filtration experiments were performed with commercially available alumina ceramic membranes. By analyzing high-resolution images from FlowCam, the transport and retention behaviors of the two microplastic alternatives were examined by comparing their morphological properties. Despite their similar particle sizes, the cornstarch demonstrated a higher removal efficiency (82%) than the silica (72%) in the ceramic membrane filtration due to its greater tendency to aggregate. This increased tendency for aggregation suggests that cornstarch may contribute to faster fouling, while the stability and uniformity of silica particles result in less fouling. The FlowCam analysis revealed that the cornstarch particles experienced a slight increase in circularity and compactness over time, likely due to physical swelling and aggregation, while the silica particles retained their shape and structural integrity. These findings highlight the impact of the morphological properties of alternative microplastics on their filtration behavior and fouling potential., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Dieckol is a brown algal phlorotannin with potent bioactivities such as hepatoprotective effects. This study aimed to produce dieckol-rich extract from Eisenia bicyclis and apply them as a functional ingredient for a novel bacterial cellulose (BC)-based dessert. The modeling and optimization of the ultrasound-assisted extraction (UAE) process were performed. The developed model showed that at least one of the linear or quadratic terms of all variables (amplitude, solvent concentration, temperature, and time) affected dieckol recovery (p < 0.05). Following numerical optimization, dieckol recovery achieved 17.3 mg/g biomass under optimal conditions (62 % amplitude, 35 % solvent concentration, 70 °C, and 6 min), similar to the model-predicted value (18.3 mg/g). Then, BC-dieckol (BC-D) pellicles were fabricated by ex situ loading 25, 50, 75, and 100 % of the liquid extract with 9.954 mg dieckol (recommended intake level). All BC-D pellicles showed high dieckol loading (98.16 - 100 %), and BC-D100 meets the acceptable level. The FTIR and SEM analyses confirmed the impregnation of the extract, especially the signature peaks of dieckol, related to aromatic ether stretch and aromatic ring structure of phlorotannin by the FTIR spectra. The crystallinity index and water absorption capacity of BC-D100 were determined to be about 83.9 % and 415.6 %, respectively, which were slightly decreased compared to BC-control, but not significantly. In addition, BC-D100 has shown antioxidant activity making it valuable as a food material. This study provides valuable information for the food industry, paving the way for developing novel BC-based foods using brown algal extracts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Recent advancements in deep learning have significantly improved medical image segmentation. However, the generalization performance and potential risks of data-driven models remain insufficiently validated. Specifically, unrealistic segmentation predictions deviating from actual anatomical structures, known as a Seg-Hallucination, often occur in deep learning-based models. The Seg-Hallucinations can result in erroneous quantitative analyses and distort critical imaging biomarker information, yet effective audits or corrections to address these issues are rare. Therefore, we propose an automated Seg-Hallucination surveillance and correction (ASHSC) algorithm utilizing only 3D organ mask information derived from CT images without reliance on the ground truth. Two publicly available datasets were used in developing the ASHSC algorithm: 280 CT scans from the TotalSegmentator dataset for training and 274 CT scans from the Cancer Imaging Archive (TCIA) dataset for performance evaluation. The ASHSC algorithm utilizes a two-stage on-demand strategy with mesh-based convolutional neural networks and generative artificial intelligence. The segmentation quality level (SQ-level)-based surveillance stage was evaluated using the area under the receiver operating curve, sensitivity, specificity, and positive predictive value. The on-demand correction performance of the algorithm was assessed using similarity metrics: volumetric Dice score, volume error percentage, average surface distance, and Hausdorff distance. Average performance of the surveillance stage resulted in an AUROC of 0.94 ± 0.01, sensitivity of 0.82 ± 0.03, specificity of 0.90 ± 0.01, and PPV of 0.92 ± 0.01 for test dataset. After the on-demand refinement of the correction stage, all the four similarity metrics were improved compared to a single use of the AI-segmentation model. This study not only enhances the efficiency and reliability of handling the Seg-Hallucination but also eliminates the reliance on ground truth. The ASHSC algorithm offers intuitive 3D guidance for uncertainty regions, while maintaining manageable computational complexity. The SQ-level-based on-demand correction strategy adaptively minimizes uncertainties inherent in deep-learning-based organ masks and advances automated auditing and correction methodologies.

In this work, we present a facile and straightforward approach for fabricating highly stretchable photodetectors based on Ag 2 S and Ti 3 C 2 T x MXene hybrid materials. These devices exhibit exceptional mechanical resilience, maintaining stable electrical and optical performance even after 10 000 cycles of 30% strain. The incorporation of MXene not only enhances the device's electrical durability but also ensures the retention of conductivity under significant mechanical deformation, positioning MXene as a critical material for the advancement of flexible electronics. These devices demonstrate strong photoresponses across a broad wavelength range, from visible to infrared, confirming their potential for use in flexible and stretchable optoelectronic applications. This study highlights the advantage of utilizing MXene in stretchable electronics and offers a promising route for developing durable, flexible devices for next-generation wearable technologies.

The unique characteristics of metasurfaces to precisely control the amplitude, phase, and polarization of light within a thin, flat footprint make them a promising replacement for bulky optical components. However, fabrication methods of conventional metasurfaces have suffered from low throughput and high costs, limiting scalability and practical application. To address these challenges, an advanced fabrication technique is developed by combining deep-ultraviolet argon fluoride photolithography with wafer-scale nanotransfer printing to facilitate the scalable fabrication of metal-insulator-metal structures. This approach not only facilitates the production of numerous reflective metaholograms with a yield of 70.6% on 8 inch wafers but also significantly reduces production costs to under one dollar per unit, improving economic feasibility. Hundreds of metaholograms each on the millimeter scale have been fabricated and operate across the visible to near-infrared range, showing conversion efficiencies of 43.6% at 635 nm, 40% at 940 nm, and 2.2% at 532 nm. This result opens new avenues for the widespread adoption of metasurface technologies in imaging, sensing, and optical communications. By enabling scalable, cost-effective production, our method is poised for widespread adoption and opening new possibilities in metasurface technology.

Arterial endothelial cells (ECs) reside in a complex biomechanical environment. ECs sense and respond to wall shear stress. Low and oscillatory wall shear stress is characteristic of disturbed flow and commonly found at arterial bifurcations and around atherosclerotic plaques. Disturbed flow is pro-inflammatory to ECs. Arteries also stiffen with aging and/or the onset of vascular disease. ECs sense and respond to stiffening in a pro-fibrotic manner. Thus, flow and stiffening disturbances elicit EC responses that promote pathologic arterial remodeling. However, the pathways elicited by ECs under pathologic stiffening and disturbed flow are not well understood. The objective of this work was to discover and test the modifiability of key pathways in ECs. To do this we used the partial carotid ligation model to impose disturbed flow onto the precociously stiffened fibulin-5 knockout (Fbln5 -/- ) mouse carotid arteries. Biomechanical testing demonstrated that Fbln5 -/- arteries under disturbed flow approximate the stiffness ratio of diseased human arteries, and the ECs in these Fbln5 -/- arteries underwent rapid reprogramming via endothelial to mesenchymal transition (EndMT). Under atherogenic conditions, disturbed flow Fbln5 -/- arteries developed more vulnerable plaques than the wild type (WT) mouse arteries. Connective tissue growth factor/cellular communication network factor 2 (Ctgf/Ccn2) was upregulated in vivo in ECs with aging, with stiffening in the Fbln5 -/- arteries, and increased again by disturbed flow under stiffened conditions, supporting CTGF as a key biomarker for flow and stiffening. This was validated by immunohistochemistry, which demonstrated increased CTGF deposition in areas of disturbed flow in patient carotid endarterectomy and peripheral artery disease (PAD) specimens. Finally, to test the role of CTGF in regulating and combining these processes, we created an EC-specific Ctgf knockout (Ctgf ecko ). We identified that carotid arteries under disturbed flow and atherogenic conditions in male Ctgf ecko , but not female, mice had decreased plaque area compared to WT control mice. We then tested the Ctgf expression in the carotid endothelium exposed to disturbed or stable flow in WT and Fbln5 -/- mice. Here we found that under disturbed flow male mice had greater Ctgf expression than female mice. This work demonstrates that stiffened + disturbed flow conditions drive EC reprogramming, that CTGF is increased by these conditions, and that this increase is more prominent in male carotid arteries. Future exploration of sex-based differences in these fibrotic pathways are warranted to develop targeted therapeutics to limit pathologic arterial remodeling under pathologically stiffened + disturbed flow environments., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2025. Published by Elsevier B.V.)

Physical unclonable functions (PUFs), often referred to as digital fingerprints, are emerging as critical elements in enhancing hardware security and encryption. While significant progress has been made in developing optical and memory-based PUFs, integrating reconfigurability with sensitivity to circularly polarized light (CPL) remains largely unexplored. Here, we present a chiroptical synaptic memristor (CSM) as a reconfigurable PUF, leveraging a two-dimensional organic-inorganic halide chiral perovskite. The device combines CPL sensitivity with photoresponsive electrical behavior, enabling its application in optoneuromorphic systems, as demonstrated by its ability to perform image categorization tasks within neuromorphic computing. Furthermore, by leveraging a 10 × 10 crossbar array of the CSMs, we develop a PUF capable of generating reconfigurable cryptographic keys based on the combination of neuromorphic potentiation and polarized light conditions. This work demonstrates an integrated approach to optoneuromorphic functionality, data storage, and encryption, providing an alternative approach for reconfigurable memristor-based PUFs.

A class of (thio)chromenone derivatives has been identified as suitable ligands for uPAR, a glycoprotein with a prognostic value in a large number of human cancers. The (thio)chromenone agents actively inhibited the binding of uPAR to uPA with a binding affinity of 18.6 nM, reducing cell migration in the wound healing assay by up to 40% without apparent cell motility. The discovery of an uPAR-targeting fluorescent probe was also made in this study that can selectively bind to the membrane uPAR, providing valuable molecular insights into the role of uPAR in cancer metastasis. This study should serve as a basis for the development of new uPAR-targeting agents that can control the metastatic potential of cancer cells with minimal cytotoxicity.

Hexaconazole, a triazole insecticide, is widely used to control rust disease in Welsh onions. Residue levels of pesticides vary based on the cooking methods. Although studies on hexaconazole residue have involved vegetables such as cabbage, research on Welsh onion is limited. This study investigated the effect of different cooking methods on hexaconazole residues. Welsh onion was processed by common cooking methods such as stir-frying, boiling, and baking, and analyzed for pesticide residues using liquid chromatography with tandem mass spectrometry. The results showed that the removal rates of pesticides after cooking were 40.0-62.9% for stir-frying, 80.0-91.4% for boiling, and 51.4-77.1% for baking. Regardless of cutting thickness (0.8 cm or 5 cm), the reduction rate of pesticide residues increased with time during boiling. Increased reduction rates were also observed with increased time during baking. As stir-frying time increased, the residue amount increased due to water loss. However, the absolute amount of the pesticide decreased with increasing time. Therefore, the residue amount of hexaconazole in Welsh onion was reduced by various general cooking processes. These findings can provide a valuable foundation for research on Welsh onion processing, address consumer concerns about pesticide residues, and provide baseline data for risk assessments.

CRISPR-Cas is a bacterial defense system that employs RNA-guided endonucleases to destroy invading foreign nucleic acids. Bacteriophages produce anti-CRISPR (Acr) proteins to evade CRISPR-Cas defense during the infection. AcrIIC5, a type II-C Cas9 inhibitor, exhibits unusual variations in the local backbone fold between its orthologs. Here we investigated how the folding variations affect the inhibition of target Cas9 using AcrIIC5 orthologs. Structural comparison of free AcrIIC5 Smu and AcrIIC5 Nch confirmed that the folding variation correlated with characteristic indels in the helical region. Mutagenesis and biochemical assays combined with AlphaFold2 predictions identified key residues of AcrIIC5 orthologs important for Cas9 inhibition. Remarkably, AcrIIC5 orthologs employed divergent binding interfaces via folding variations to inhibit the Cas9 targets. Our study suggests that Acr proteins have evolved structural variants to diversify key interfaces for target Cas9, which could be beneficial for the adaptation of phages to evasive mutations on the Cas9 surface., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Data-driven calibration methods have shown promising results for accurate proprioception in soft robotics. This process can be greatly benefited by adopting numerical simulation for computational efficiency. However, the gap between the simulated and real domains limits the accurate, generalized application of the approach. Herein, we propose an unsupervised domain adaptation framework as a data-efficient, generalized alignment of these heterogeneous sensor domains. A dual cross-modal autoencoder was designed to match the sensor domains at a feature level without any extensive labeling process, facilitating the computationally efficient transferability to various tasks. Moreover, our framework integrates domain adaptation with anomaly detection, which endows robots with the capability for external collision detection. As a proof-of-concept, the methodology was adopted for the famous soft robot design, a multigait soft robot, and two fundamental perception tasks for autonomous robot operation, involving high-fidelity shape estimation and collision detection. The resulting perception demonstrates the digital-twinned calibration process in both the simulated and real domains. The proposed design outperforms the existing prevalent benchmarks for both perception tasks. This unsupervised framework envisions a new approach to imparting embodied intelligence to soft robotic systems via blending simulation.

Background and Objectives: Skin microbiome dysbiosis can cause skin barrier dysfunction and stimulate scar property change. Skin barrier disruption post-burn injury leads to an imbalance in skin microbe diversity and distribution. We aimed to examine the changes in the skin microbiome of re-epithelialized burn scars., Material and Methods: Twenty three patients were enrolled between January 2020 and July 2022. Twenty-six (13 Scar 1, immediately after complete wound healing; and 13 Scar 2, 3 months after complete wound healing) of seventy-eight scar skin samples (39 Scar 1 and 39 scar 2) qualified for analysis. Microbial community analysis was performed. Biomechanical scar properties of each patient and their correlation with skin microbiome were investigated., Results: The α-diversity of the scarred skin microbiome increased with time (Shannon's index, p = 0.029; Simpson's index, p = 0.009). The linear discriminant analysis effect size results showed that Bacteroides abundance decreased in scars after 3 months, whereas Campylobacter and Cutibacterium abundance increased. Campylobacter and Cutibacterium negatively and positively correlated with the final distensibility gross and biological elasticity, respectively. These results were consistent with the changes in the biomechanical properties of scars., Conclusion: The scar skin microbial communities in patients with burns changed with biomechanical scar properties over time, and specific skin microorganisms correlated with biomechanical scar dynamics at the genus level., Competing Interests: Declaration of Competing Interest Our authors declare that we have no conflicts of interest relevant to this work. The funder had no role in the design of the study, collection, analyses, or interpretation of data, writing of the manuscript, or the decision to publish the results., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis (Mtb) poses a significant threat to health globally. During searching for new chemical entities regulating MDR- and XDR-Mtb, chemical investigation of the black oil beetle gut bacterium Micromonospora sp. GR10 led to the discovery of eight new members of arenicolides along with the identification of arenicolide A (Ar-A, 1), which was a previously reported macrolide with incomplete configuration. Genomic analysis of the bacterial strain GR10 revealed their putative biosynthetic pathway. Quantum mechanics-based computation, chemical derivatizations, and bioinformatic analysis established the absolute stereochemistry of Ar-A and arenicolides D-K (Ar-D-K, 2-9) completely for the first time. Biological studies of 1-9 revealed their antimicrobial activity against MDR and XDR strains of Mtb. Ar-A had the most potent in vitro antimicrobial efficacy against MDR- and XDR-Mtb. Mechanistically, Ar-A induced ATP depletion and destabilized Mtb cell wall, thereby inhibiting growth. Notably, Ar-A exerted a significant antimicrobial effect against Mtb in macrophages, was effective in the treatment of Mtb infections, and showed a synergistic effect with amikacin (AMK) in a mouse model of MDR-Mtb lung infection. Collectively, our findings indicate Ar-A to be a promising drug lead for drug-resistant tuberculosis., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Anti-CRISPR (Acr) proteins are natural inhibitors of CRISPR-Cas systems, found in bacteriophages and other genetic elements. AcrIE3, identified in a Pseudomonas phage, inactivates the type I-E CRISPR-Cas system in Pseudomonas aeruginosa by engaging with the Cascade complex. However, its precise inhibition mechanism has remained elusive. In this study, we present a comprehensive structural and biochemical analysis of AcrIE3, providing mechanistic insight into its anti-CRISPR function. Our results reveal that AcrIE3 selectively binds to the Cas8e subunit of the Cascade complex. The crystal structure of AcrIE3 exhibits an all-helical fold with a negatively charged surface. Through extensive mutational analyses, we show that AcrIE3 interacts with the protospacer adjacent motif (PAM) recognition site in Cas8e through its negatively charged surface residues. These findings enhance our understanding of the structure and function of type I-E Acr proteins, suggesting PAM interaction sites as primary targets for divergent Acr inhibitors., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Glioblastoma multiforme (GBM) is a devastating primary tumor of the central nervous system with a significantly poor prognosis. The primary challenge in treating GBM lies in the restrictive nature of the blood-brain barrier (BBB), impeding effective drug delivery to the brain. In this study, intranasal polymeric micelles encapsulating a quercetin-etoposide combination were developed to induce synergistic apoptotic effects and enhance direct drug delivery to the brain. However, the in vivo anticancer efficacy of the unmodified micelle formulation via intranasal administration remains limited. Therefore, this aims to investigate the enhancement of the formulation by conjugating the micelles with a novel and highly potent cell-penetrating peptide (CPP), RMMR1, identified using the intra-dermal delivery technology platform developed by REMEDI Co., Ltd. This modification seeks to enhance the brain-targeting capability of the micelles. The CPP-modified micelles encapsulating the quercetin-etoposide combination (CM(QE)) demonstrated superior in vivo brain-delivery efficiency and enhanced cellular uptake after intranasal administration. Furthermore, animal studies showed significant tumor reduction and increased survival rates, with no significant changes in body weight observed. These findings suggest that intranasal administration of CM(QE) holds promise as a significant advancement in chemotherapy for GBM., Competing Interests: Declaration of competing interest S. Cho and C. Park are listed on the patent entitled “Cargo molecule transport domain RMMR1, variant thereof, recombinant cargo molecule containing thereof and cargo molecule transport method using the same” (Application number: PCT/KR2022/007344). The remaining authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pressure in the pulmonary arteries, commonly resulting in right heart failure. PAH is associated with a high economic burden throughout the duration of the disease., Methods: This retrospective cohort study of the Milliman Contributor Health Source Data, the Medicare 100% Research Identifiable Files, and the Merative Marketscan ® Commercial dataset between 2018 and 2020 identified adult patients with prevalent PAH based on the earliest qualifying diagnosis date or medication date ('index date') between January 1, 2019 and November 30, 2020. Outcomes were assessed using patient data from index date through the earliest of end of enrollment, end of data, or death (Medicare fee-for-service [FFS] only). All-cause and PAH-related medical and pharmacy costs per-patient per-month (PPPM) and healthcare resource utilization per 1000 patients were summarized., Results: The study included 11,670 Medicare FFS, 1021 Medicare Advantage, 274 Medicaid, and 1174 commercially insured patients in the US. The annual national burden to payers was estimated to be US$3.1 billion. The PPPM payer costs ranged from US$6500 to US$14,742; out-of-pocket (OOP) costs ranged from US$341 to US$907 PPPM. Inpatient utilization rate ranged from 435 to 770 per 1000 patients for all-cause admissions and from 15 to 58 per 1000 patients for PAH-related admissions., Conclusions: This study demonstrates that PAH continues to be associated with a high economic burden and healthcare resource utilization across all payer types within the US healthcare system., Competing Interests: Declarations. Funding: This research was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Conflict of interest: AW, DL, and AA are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA at time of manuscript submission. CF, GD, and CP are employees of Milliman, Inc., who received consulting fees from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. KEK participated in United Therapeutics speaker’s bureau 2018–2021 and served on advisory boards and as a consultant for United Therapeutics, J&J Actelion, Acceleron, and Merck & Co., Inc., Rahway, NJ, USA. Ethics approval: Ethics approval is not required as this project does not include any interaction with human subjects and only uses publicly available de-identified claims data. Informed consent: Not applicable. Availability of data and materials: The data that support the findings of this study are available from the authors but restrictions apply to the availability of these data, which were obtained under license from the Centers for Medicare & Medicaid Services (CMS), Merative L.P., and Milliman, Inc.. As such, data used for this study are not publicly available. Author contributions: Substantial contributions to the conception or design of the work: all authors. Data analysis: CF, CP. Interpretation of data for the work: all authors. Drafting the work or reviewing it critically for important intellectual content: all authors. Final approval of the version to be published: all authors. The authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved., (© 2024. Merck & Co., Inc., Rahway, NJ, USA and its affiliates, and Milliman, Inc., New York, NY, USA.)

Background: There is evidence that heart failure with preserved ejection fraction (HFpEF)-related hospitalizations are increasing in the United States. However, there is a lack of knowledge about HFpEF-related hospitalizations among younger adults., Objective: The aims of this study were to perform a retrospective analysis using the Nationwide Inpatient Sample and to examine age-stratified sex differences in the prevalence, correlates, and outcomes of HFpEF-related hospitalization across the adult life span., Method: Using the Nationwide Inpatient Sample (2002-2014), patient and hospital characteristics were determined. Joinpoint regression was used to describe age-stratified sex differences in the annual average percent change of hospitalizations with HFpEF. Survey logistic regression was used to estimate adjusted odds ratios representing the association of sex with HFpEF-related hospitalization and in-hospital mortality., Results: There were 8 599 717 HFpEF-related hospitalizations (2.43% of all hospitalizations). Women represented the majority (5 459 422 [63.48%]) of HFpEF-related adult hospitalizations, compared with men (3 140 295 [36.52%]). Compared with men younger than 50 years, women within the same age group were 6% to 28% less likely to experience HFpEF-related hospitalization. Comorbidities such as hypertensive heart disease, renal disease, hypertension, obstructive sleep apnea, atrial fibrillation, obesity, anemia, and pulmonary edema explained a greater proportion of the risk of HFpEF-related hospitalization in adults younger than 50 years than in adults 50 years or older., Conclusion: Before the age of 50 years, women exhibit lower HFpEF-related hospitalization than men, a pattern that reverses with advancing age. Understanding and addressing the factors contributing to these sex-specific differences can have several potential implications for improving women's cardiovascular health., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Although the importance of early diagnosis of malignant tumors is a major concern, an easily accessible in-house method has not been established., Objectives: To investigate the most optimal model by combining thymidine kinase 1 (TK1) autoantibody, extracellular protein kinase A (ECPKA) autoantibody, TK1 antigen, C-reactive protein (CRP), age, breed, and sex., Animals: Serum samples from 1702 dogs were collected from local animal hospitals and referral animal medical centers in Korea., Methods: TK1 autoantibody, ECPKA autoantibody, and CRP were measured using LFIA methods in serum samples of dog to design a new neoplastic index (NI) for early detection of malignant tumors in dogs., Results: AUC of TK1 autoantibody model with TK1 antigen, CRP, age, and breed in multiple logistic regression analysis was 0.966 (TK1 autoantibody, P = .0005; TK1 antigen, P = .0003), and when the cutoff value was 0.417, the specificity was 87.1%, and sensitivity was 96.4%. Regression coefficients were 24.4, 20.5, 24.8, 10.6, respectively in TK1 autoantibody, TK1 antigen, CRP, and age, and the effect by breed (regression coefficient 2.1, 3.0) was the lowest. The same multiple logistic regression analysis on dogs with lymphoma, and AUC of TK1 autoantibody model was 0.981 (all P < .0001, TK1 antigen P = .09), when the cutoff value was 0.352, the specificity was 92.9%, and sensitivity was 93.7%., Conclusions and Clinical Importance: The NI including TK1 autoantibody could be useful in the screening test for both lymphoma and other tumors., (© 2024 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

With the emergence of electromechanical devices, considerable efforts have been devoted to improving the piezoelectricity of 2D materials. Herein, an anion-doping approach is proposed as an effective way to enhance the piezoelectricity of α-In 2 Se 3 nanosheets, which has a rare asymmetric structure in both the in-plane and out-of-plane directions. As the O 2 plasma treatment gradually substitutes selenium with oxygen, it changes the crystal structure, creating a larger lattice distortion and, thus, an extended dipole moment. Prior to the O 2 treatment, the lattice extension is deliberately maximized in the lateral direction by imposing in situ tensile strain during the exfoliation process for preparing the nanosheets. Combining doping and strain engineering substantially enhances the piezoelectric coefficient and electromechanical energy conversion. As a result, the optimal harvester with a 0.9% in situ strain and 10 min plasma exposure achieves the highest piezoelectric energy harvesting values of ≈13.5 nA and ≈420 µW cm -2 under bending operation, outperforming all previously reported 2D materials. Theoretical estimation of the structural changes and polarization with gradual oxygen substitution supports the observed dependence of the electromechanical performance., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Nanoplastics (NPs) are emerging environmental contaminants present in atmospheric, freshwater, and aquatic environments. NPs can rapidly permeate cell membranes and build up in human tissues and organs, causing a potential threat to human health. As the skeletal muscle undergoes aging, myogenesis gradually deteriorates, leading to loss of muscle mass. While previous studies have demonstrated the adverse and toxic effects of polystyrene (PS)-NPs, gaps remain in understanding aging effects and specific mechanisms by PS-NPs in pre-differentiated myoblasts. In this study, we investigated the cellular internalization, aggregation, and senescent effects of PS-NPs using an in vitro model of pre-differentiated C2C12 myoblasts. Pre-differentiated C2C12 myoblasts were exposed to increasing concentrations of PS-NPs and internalization was observed in myoblasts using flow cytometry and transmission electron microscopy (TEM). We further investigated whether internalization of these PS-NPs at sublethal cytotoxic concentrations led to an increase in senescence hallmarks, such as increased β-galactosidase activity, increased expression of p16, p21 and senescence-related secretory phenotypes, and cell cycle arrest. In addition, PS-NP treatment caused notable mitochondrial superoxide production and damage, including mitochondrial membrane depolarization, content loss, fragmentation, and decreased ATP production. Rotenone, a mitochondrial function inhibitor, and exacerbated PS-NP-induced cell proliferation inhibition, whereas Mito-TEMPO, a mitochondrial superoxide scavenger, restored the cell proliferation rate and rescued cellular senescence. Therefore, our findings indicate the senescent effects of PS-NPs through mitochondrial superoxide production and dysfunction in pre-differentiated myoblasts., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The goal was to create a brief temperament inventory grounded in the Regulative Theory of Temperament (FCB-TMI-CC ) , with a user-friendly, online applicability for studies in different cultures. As the regulative role of temperament is strongly revealed under meaningful stress, the study was planned within the time of the COVID-19 pandemic. To ensure high diversity in terms of culture, economic and environmental conditions, data from nine countries (Poland, United States of America, Italy, Japan, Argentina, South Korea, Ireland, United Kingdom and Kazakhstan) were utilized (min. N  = 200 per country). Validation data were gathered on the level of COVID-19 stressors, posttraumatic stress disorder (PTSD), depression, anxiety and stress symptoms, and Big Five personality traits. Multigroup confirmatory factor analysis served as the basis for the inventory's construction. The final culture-common version includes 37 items (5-6 in each of the 7 scales) and covers the core aspects of temperament dimensions. Temperament structure was confirmed to be equivalent across measured cultures. The measurement is invariant at the level of factor loadings and the reliability (internal consistency) and theoretical validity of the scales were at least acceptable. Therefore, the FCB-TMI-CC may serve as a valuable tool for studying temperament across diverse cultures and facilitate cross-cultural comparisons.

The popliteal artery segment is particularly challenging for endovascular treatment. Stents used for treating popliteal artery lesions are usually associated with an increased risk of stent fracture and re-occlusion. The Supera stent is designed to withstand mechanical stress, with a low risk of fracture. A man in his mid-70s with left popliteal artery occlusion was treated with a Supera stent implantation. After 5 months, he revisited our hospital complaining of left leg pain. Preprocedural computed tomography angiography showed popliteal artery occlusion associated with a Supera stent fracture. A new Supera stent was implanted at the previous stent fracture site. However, 3 months after the second procedure, computed tomography angiography showed popliteal artery re-occlusion associated with a repeated fracture of the Supera stent. A femoral-popliteal bypass was performed. At the 6-month follow-up, computed tomography angiography showed a patent graft. Our findings indicated that recurrent fractures occurred after additional Supera stenting at the previous Supera stent fracture site. Careful observation is necessary after deploying a new Supera stent for treating a Supera stent fracture because of the possibility of a repeated fracture., Competing Interests: Declaration of conflicting interestThe authors declare that there is no conflict of interest.

Virtual Reality (VR) technology enables users to immerse themselves in computer-generated environments, providing experiences that are otherwise difficult to attain in real life. VR has expanded from gaming into diverse fields, even the medical sector. In medical education, VR is mainly employed for anatomy and surgical practice, enhancing the learning experience by offering three-dimensional visualization and interaction with human structures. This article compares various VR anatomical applications, including "VEDAVI VR Human Anatomy", "Sharecare YOU Anatomy", "Everyday Anatomy VR", "3D Organon VR Anatomy", "Anatomy Explorer 2020", and "Human Anatomy VR". The comparison focuses on several aspects: the functions of each application, the accuracy of anatomical descriptions of the models, the depiction of movement and functionality of human body parts, the expression of disease, and other practical considerations such as tutorials, convenience of operation and observation, pricing, and user-friendliness. This study aims to serve as a guide for practical use, recommending the most suitable VR applications for educational purposes in the medical field and providing suggestions for improvement based on the analysis., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Vascular ageing (vascular ageing) is the deterioration of arterial structure and function which occurs naturally with age, and which can be accelerated with disease. Measurements of vascular ageing are emerging as markers of cardiovascular risk, with potential applications in disease diagnosis and prognosis, and for guiding treatments. However, vascular ageing is not yet routinely assessed in clinical practice. A key step towards this is the development of technologies to assess vascular ageing. In this Roadmap, experts discuss several aspects of this process, including: measurement technologies; the development pipeline; clinical applications; and future research directions. The Roadmap summarises the state of the art, outlines the major challenges to overcome, and identifies potential future research directions to address these challenges., (Creative Commons Attribution license.)

Probiotics are known to have favorable effects on human health. Nevertheless, probiotics are not always beneficial and can cause unintended adverse effects such as bacteremia and/or inflammation in immunocompromised patients. In the present study, we investigated the effects of probiotics on the regulation of bone metabolism under different health conditions and delivery routes. Intragastric administration of Lactiplantibacillus plantarum to ovariectomized mouse models for mimicking post-menopausal osteoporosis in humans substantially ameliorated osteoporosis by increasing bone and mineral density. In contrast, such effects did not occur in normal healthy mice under the same condition. Interestingly, however, intraperitoneal administration of L. plantarum induced bone destruction by increasing osteoclast differentiation and decreasing osteoblast differentiation. Furthermore, when L. plantarum was implanted into mouse calvarial bone, it potently augmented bone resorption. Concordantly, L. plantarum upregulated osteoclastogenesis and downregulated osteoblastogenesis in in vitro experiments. These results suggest that L. plantarum can have distinct roles in the regulation of bone metabolism depending on bone health and the delivery route., Competing Interests: Declarations. Conflict of Interests: The authors declare no competing interests., (© 2024. The Author(s).)

Perovskite oxides are promising candidates for chemiresistive-type gas sensors owing to their exceptional thermal and chemical stability during solid-gas reactions. However, perovskites suffer from critical issues such as low surface area and poor surface activity, which negatively influence the sensing characteristics. While metal nanoparticles can be incorporated in perovskites to improve their reactivity, the fundamental incompatibility between catalytic metals and perovskite oxides often leads to substantial structural degradation as well as phase instability. Herein, we overcome this challenge through the introduction of an intermediary phase that forms coherent interfaces with both the perovskite phase and catalyst metals. Specifically, we present the case study of p-type La 0.8 Ca 0.2 Fe 0.98 Pt 0.02 O 3 perovskite, whose hole accumulation layer was modulated by the incorporation of metal-organic framework (MOF)-derived n-type α-Fe 2 O 3 nanoparticles decorated with highly dispersed Pt catalysts. The resulting composite exhibited significantly improved surface activity over the nonmodified La 0.8 Ca 0.2 FeO 3 perovskite, leading to exceptional chemiresistive sensing performance toward acetone gas ( R g = 39.8 toward 10 ppm of acetone at 250 °C) with high cross-sensitivity against interfering gases. Importantly, our findings reaffirm the critical influence of interfacial engineering in facilitating surface chemical reactions on perovskite oxides and, by doing so, effectively provide a general synthetic guideline to the design of perovskite-based chemiresistors.R a = 39.8 toward 10 ppm of acetone at 250 °C) with high cross-sensitivity against interfering gases. Importantly, our findings reaffirm the critical influence of interfacial engineering in facilitating surface chemical reactions on perovskite oxides and, by doing so, effectively provide a general synthetic guideline to the design of perovskite-based chemiresistors.

Single-nucleus RNA-sequencing (snRNA-seq) has revealed new levels of cellular organization and diversity within the human brain. However, full-length mRNA isoforms are not resolved in typical snRNA-seq analyses using short-read sequencing that cannot capture full-length transcripts. Here we combine standard 10x Genomics short-read snRNA-seq with targeted PacBio long-read snRNA-seq to examine isoforms of genes associated with neurological diseases at the single-cell level from prefrontal cortex samples of diseased and nondiseased human brain, assessing over 165,000 cells. Samples from 25 postmortem donors with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or Parkinson's disease (PD), along with age-matched controls, were compared. Analysis of the short-read libraries identified shared and distinct gene expression changes across the diseases. The same libraries were then assayed using enrichment probes to target 50 disease-related genes followed by long-read PacBio sequencing, enabling linkage between cell type and isoform expression. Vast mRNA isoform diversity was observed in all 50 targeted genes, even those that were not differentially expressed in the short-read data. We also developed an informatics method for detection of isoform structural differences in novel isoforms versus the reference annotation. These data expand available single-cell datasets of the human prefrontal cortical transcriptome with combined short- and long-read sequencing across AD, DLB, and PD, revealing increased mRNA isoform diversity that may contribute to disease features and could potentially represent therapeutic targets for neurodegenerative diseases., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Liu et al.)

In this study, a novel adsorbent called Ca@SP was developed by immobilizing microalgae protein (Spirulina platensis, SP) in an alginate matrix for enhanced Pb²⁺ removal from aqueous solutions. Synthesized via in situ crosslinking, Ca@SP leverages the synergistic effects of alginate's gel-forming ability and SP's N-rich biomass. Characterization of Ca@SP revealed a green spherical hydrogel with a BET specific surface area of 159.5 m²/g. The composite exhibited pH-dependent and highly selective adsorption for Pb²⁺ over other divalent metal ions, which can be explained by the relatively lower hydrated Gibbs free energy of Pb²⁺. The main adsorption mechanisms were identified as physical adsorption, electrostatic interaction, complexation, and ion exchange. Column experiments demonstrated Ca@SP's effectiveness under various operational conditions, including flow rate, influent concentration, and column heights. RSM was employed to optimize the adsorption process, with initial pH emerging as a critical parameter influencing Pb²⁺ removal efficiency. Desorption experiments showed that acidic solvents had higher desorption efficiency than alkaline solvents, and the potential for reusability was confirmed. These results suggest that Ca@SP has potential as an effective and sustainable adsorbent for Pb²⁺ removal from aqueous environments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The electrochemical nitrate reduction reaction (NO 3 - RR) involves multiple hydrogenation and deoxygenation steps, which compete with the hydrogen evolution reaction (HER). Therefore, NO 3 - RR driven in acidic media is challenging in spite of advantageous fast hydrogen transfers in its elementary steps. The findings presented in this article first demonstrate that the NO 3 - RR is significantly activated even in acidic lithium nitrate solutions at LiNO 3 concentrations exceeding 6 m on a Pt electrode (the highly effective catalyst for HER) by the formation of a "hydronium-in-salt" electrolyte (HISE), a new type of aqueous high concentration salt electrolyte. The observed enhancement of NO 3 - RR while the suppression of HER-activity in the LiNO 3 based HISE was verified by scanning electrochemical microscopy, electrochemical impedance spectroscopy, UV-vis/IR spectroscopy, and molecular dynamics simulations. The formation of a HISE in acidic LiNO 3 solutions contrasts with that of a "water-in-salt" electrolyte in LiTFSI with the same concentration. The mechanism of NO 3 - RR activation in a HISE suggests facilitated proton-coupled electron transfers (PCETs) from H 3 O + to NO 3 - and subsequent reactive intermediates owing to the proximity between the two ions induced by the unique solvation structure blended with all ions together (Li + + NO 3 - + H 3 O + ). In contrast, all the ions are separately hydrated at low concentrations of LiNO 3 electrolytes. On the other hand, PCET from H 2 O to NO 3 - in a high concentration LiNO 3 electrolyte (e.g., 9 m) is not kinetically preferred, probably owing to the slow dissociation kinetics of H 2 O, and therefore, H 2 O reduction is not suppressed by the NO 3 - RR.

The evolution of high-performance electrode materials has significantly impacted the development of real-time monitoring biosensors, emphasizing the need for compatibility with biomaterials and robust electrochemical properties. This work focuses on creating electrode materials utilizing single-walled carbon nanotubes (SWCNTs) and multi-walled carbon nanotubes (MWCNTs), specifically examining their dispersion behavior and electrochemical characteristics. By using ultrasonic waves, we analyzed the dispersion of CNTs in various solvents, including N, N-dimethylformamide (DMF), deionized water (DW), ethanol, and acetone. The findings revealed that SWCNTs achieved optimal dispersion without precipitation in DMF. Additionally, we observed that the electrical resistance decreased as the concentration of SWCNTs increased from 0.025 to 0.4 g/L, with significant conductivity enhancements noted between 0.2 g/L and 0.4 g/L in DMF. In constructing the biosensor platform, we employed 1-pyrenebutanoic acid succinimidyl ester (PBSE) as a linker molecule, while glucose oxidase (Gox) served as the binding substrate. The interaction between Gox and glucose led to a notable decrease in the biosensor's resistance values as glucose concentrations ranged from 0.001 to 0.1 M. These results provide foundational insights into the development of SWCNT-based electrode materials and suggest a promising pathway toward the next generation of efficient and reliable biosensors.

Background: Calcific aortic valve disease (CAVD) is a highly prevalent disease, especially in the elderly population, but there are no effective drug therapies other than aortic valve repair or replacement. CAVD develops preferentially on the fibrosa side, while the ventricularis side remains relatively spared through unknown mechanisms. We hypothesized that the fibrosa is prone to the disease due to side-dependent differences in transcriptomic patterns and cell phenotypes., Methods: To test this hypothesis, we performed single-cell RNA sequencing using a new method to collect endothelial-enriched samples independently from the fibrosa and ventricularis sides of freshly obtained human aortic valve leaflets from five donors, ranging from non-diseased to fibrocalcific stages., Results: From the 82,356 aortic valve cells analyzed, we found 27 cell clusters, including seven valvular endothelial cell (VEC), nine valvular interstitial cell (VIC), and seven immune, three transitional, and one stromal cell population. We identified several side-dependent VEC subtypes with unique gene expression patterns. Homeostatic VIC clusters were abundant in non-diseased tissues, while VICs enriched with fibrocalcific genes and pathways were more prevalent in diseased leaflets. Furthermore, homeostatic macrophage (MΦ) clusters decreased while inflammatory MΦ and T-cell clusters increased with disease progression. A foamy MΦ cluster was increased in the fibrosa of mildly diseased tissues. Some side-dependent VEC clusters represented non-diseased, protective phenotypes, while others were CAVD-associated and were characterized by genes enriched in pathways of inflammation, endothelial-mesenchymal transition, apoptosis, proliferation, and fibrosis. Interestingly, we found several activator protein-1 (AP-1)-related transcription factors ( FOSB , FOS , JUN , JUNB ) and EGR1 to be upregulated in the fibrosa and diseased aortic valve leaflets., Conclusions: Our results showed that VECs are highly heterogeneous in a side- and CAVD-dependent manner. Unique VEC clusters and their differentially regulated genes and pathways found in the fibrosa of diseased tissues may represent novel pathogenic mechanisms and potential therapeutic targets.

Bethanechol chloride (BTC), a quaternary ammonium compound used in bladder dysfunction treatment, requires challenges in developing optimal oral dosage forms due to its high water-solubility, short half-life, rapid elimination and four times a day administration. The aim of this study was to develop optimal BTC-loaded oral dosage forms that could provide both rapid onset and sustained therapeutic effects while reducing the frequency of conventional four-times-daily dosing (Mytonin® tablets). Four different BTC-loaded oral dosage forms were designed including gastro-retentive tablet (GRT), controlled-release tablet (CRT), bilayer tablet (BLT), and tablet-in-tablet (TIT). Then, release-modulating mechanism and in vivo pharmacokinetics in beagle dogs were compared. The release profiles of the four BTC-loaded dosage forms varied according to system design and formulation composition. The optimized GRT F-5 showed rapid buoyancy within 15 s and floated for 12 h, while continuously releasing the drug. CRT showed Fickian diffusion release, whereas BLT and TIT exhibited biphasic immediate and sustained release profiles. Polymer swelling behavior was analyzed using the Vergnaud model, where GRT F-5 and CRT showed n values < 0.5, confirming diffusion-controlled polymer hydration mechanism. In the instrumental analysis, the hydrogen bonding formation of BTC with release-modulating polymers, such as hydroxypropyl methylcellulose and polyethylene oxide and loosening of the polymer structure was crucial as the water influx increased. In pharmacokinetic studies in beagle dogs, the area under the plasma concentration-time curve (AUC) by normalizing dose for 48 h for GRT, CRT, BLT, and TIT were 90.2 %, 108.6 %, 83.8 %, and 76.4 %, respectively, compared with that of the reference drug (Mytonin® tablets, immediate release, four times a day). Interestingly, the plasma maximum concentration (C max ) and AUC) 0-12h of GRT F-5 and and Mytonin® tablets for the first 12-h period were much higher compared with that of other BTC-loaded CRT, BLT, and TIT. BTC was absorbed throughout the gastrointestinal tract, but is preferably absorbed in the stomach and upper intestinal sites. However, the GRT F-5 could provide more therapeutic potential for improving patient compliance in bladder dysfunction treatment by achieving both rapid onset and sustained drug release with reduced dosing frequency., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The association between temperature variability (TV) and elevated mortality risks is widely known. Yet, few studies investigated the distinct effects of intraday and interday temperature fluctuations considering age-specific, gender-specific, and cause-specific mortality stratified by four seasons., Objectives: We investigate the associations between total, intraday, and interday temperature variabilities and total, age-specific, gender-specific, cardiovascular, and respiratory mortality year-round and also stratified by four seasons., Methods: We collected district-level daily data for temperature and total, age-specific, gender-specific, cardiovascular, and respiratory mortality in South Korea from 2011 to 2021 (N = 3,113,425). TV indices (i.e., total TV, intraday TV, and interday TV) were computed as the standard deviations of daily minimum, maximum, and mean temperatures over a lag of one to seven days. The associations between TV and mortality were evaluated by a space-time-stratified case-crossover design with quasi-Poisson regression., Results: Mortality risks varied based on the type of TV index. The associations also differed depending on the mortality type and the season. Year-round associations showed interday TV was generally associated with elevated mortality risks (total mortality: 0.30% (95% CI: 0.07%, 0.52%), 65+ mortality: 0.32% (95% CI: 0.07%, 0.58%), female mortality: 0.49% (95% CI: 0.16%, 0.82%), CVD mortality: 0.47% (95% CI: 0.02%, 0.92%) on lag0-7) while intraday TV was not significantly associated with increased risk of mortality except for the male mortality, 0.68% (95% CI: 0.04%, 1.32%) on lag0-7. Season-stratified analysis revealed that TV-related mortality risks were high consistently in the spring season and generally in the summer season while the associations were generally negative in fall and insignificant in winter., Conclusion: This study provided evidence on the season-stratified, independent impacts of intraday and interday temperature variabilities on total, age-specific, gender-specific, and cause-specific mortality risks in South Korea drawing attention to the need of targeted policies to alleviate the impacts on human health., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ho Kim reports financial support was provided by Korea Ministry of Environment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Metal halide perovskite (MHP) solar cells are promising aerospace power sources given their potential as inexpensive, lightweight, and resilient solar electricity generators. Herein, the intrinsic radiation tolerance of unencapsulated methylammonium lead iodide/chloride (CH 3 NH 3 PbI 3-x Cl x ) films was isolated. Spatially resolved photoluminescence (PL) spectroscopy and confocal microscopy revealed the fundamental defect physics through optical changes as films were irradiated with 4.5 MeV neutrons and 20 keV protons at fluences between 5×10 10 and 1×10 16 p + /cm 2 . As proton radiation increased beyond 1×10 13 p + /cm 2 , defects formed in the film, causing both a decrease in photoluminescence intensity and a 30% increase in surface darkening. All proton irradiated films additionally exhibited continuous increase of energy bandgaps and decreasing charge recombination lifetimes with increasing proton fluences. These optical changes in the absorber layer precede performance declines detectable in standard current-voltage measurements of complete solar cell devices and therefore have the potential of serving as early indicators of radiation tolerance., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

The aging process is characterized by cellular functional decline and increased susceptibility to infections. Understanding the association between virus infection and aging is crucial for developing effective strategies against viral infections in older individuals. However, the relationship between Kaposi's sarcoma-associated herpesvirus (KSHV) infection, a cause of Kaposi's sarcoma prevalent among the elderly without HIV infection, and cellular senescence remains enigmatic. This study uncovers a fascinating link between cellular senescence and enhanced KSHV infectivity in human endothelial cells. Through a comprehensive proteomic analysis, we identified caveolin-1 and CD109 as novel host factors significantly upregulated in senescent cells that promote KSHV infection. Remarkably, CRISPR-Cas9-mediated knockout of these factors reduced KSHV binding and entry, leading to decreased viral infectivity. Furthermore, surface plasmon resonance analysis and confocal microscopy revealed a direct interaction between KSHV virions and CD109 on the cell surface during entry, with recombinant CD109 protein exhibiting an intriguing ability to inhibit infection by blocking virion binding. These findings uncover a previously unrecognized role of cellular senescence in enhancing KSHV infection through upregulation of specific host factors and provide novel insights into the complex interplay between aging and viral pathogenesis.

Introduction We report an Intervention/outcome study of 33 severe COVID-19 subjects who received Seraph100 Microbind Affinity Blood Filter (Seraph 100) hemoperfusion therapy (15 survivors, 18 non-survivors) under emergency authorization from the FDA. Our objective was to determine if Seraph 100 hemoperfusion reduces SARS-CoV-2 RNA titers and/or markers of inflammation and/or epi/endothelial damage.a Methods Viral RNA and 78 protein analytes related to endothelial/epithelial damage and/or inflammation were quantified in systemic blood samples from 33 severe COVID-19 subjects collected upon ICU admission and then immediately before and after blood passed through the heparin-based Seraph 100 filter at two time points on the first day of hemoperfusion. Viral RNA titers were quantified using droplet-digital PCR. Protein analytes were quantified using multiplex/multi-analyte panels on MesoScale Discovery and ProteinSimple-Ella platforms. Results A total of 15/33 subjects had detectable viral RNA in baseline samples (shortly after ICU admission). These initial viremia levels were low, and they did not change uniformly post-perfusion. Five of 55 protein analytes that were up-regulated 1.4-120X at ICU admission relative to healthy controls showed significant decreases across the filter during the indicated time points on the first day of hemoperfusion: IP-10/CXCL10, fms-like tyrosine kinase (Flt-1), MIG/CXCL9, Hepatocyte Growth Factor (HGF) and receptor for advanced glycosylation end-products (RAGE). Paired t-tests identified 25 additional analytes that showed significant decreases (p<0.05) only without Bonferroni correction. Conclusion Initial freely circulating SARS-CoV-2 RNA levels of ICU-admitted subjects were low or undetectable. The Seraph 100 filter did not significantly reduce viral RNA titers in their plasma. However, multiple circulating proteins with roles in inflammation, endothelial/epithelial damage and/or angiogenesis decreased significantly across the filter. Larger prospective trials will be required to determine if such transient reductions translate into improved patient outcomes. However, this study did not demonstrate a direct reduction of free SARS-CoV-2 viral RNA by the Seraph 100., (S. Karger AG, Basel.)

Humans use their dexterous fingers and adaptable palm in various multiobject grasping strategies to efficiently move multiple objects together in various situations. Advanced manipulation skills, such as finger-to-palm translation and palm-to-finger translation, enhance the dexterity in multiobject grasping. These translational movements allow the fingers to transfer the grasped objects to the palm for storage, enabling the fingers to freely perform various pick-and-place tasks while the palm stores multiple objects. However, conventional grippers, although able to handle multiple objects simultaneously, lack this integrated functionality, which combines the palm's storage with the fingers' precise placement. Here, we introduce a gripper for multiobject grasping that applies translational movements of fingertips to leverage the synergistic use of fingers and the palm for enhanced pick-and-place functionality. The proposed gripper consists of four fingers and an adaptive conveyor palm. The fingers sequentially grasp and transfer objects to the palm, where the objects are stored simultaneously, allowing the gripper to move multiple objects at once. Furthermore, by reversing this process, the fingers retrieve the stored objects and place them one by one in the desired position and orientation. A finger design for simple object translating and a palm design for simultaneous object storing were proposed and validated. In addition, the time efficiency and pick-and-place capabilities of the developed gripper were demonstrated. Our work shows the potential of finger translation to enhance functionality and broaden the applicability of multiobject grasping.

Purpose: To inspect the impact of polyethylene fiber (Ribbond) on the long-span, 3D-printed, interim fixed dental prosthesis regarding fracture strength., Materials and Methods: A stainless steel platform was fabricated to replicate the partial edentulism for a maxillary four-unit fixed dental prosthesis. The prosthesis was fabricated by a Formlabs SLA 3D printer. The specimens were allocated into four groups of 20 each: experimental reinforced Group A (prosthesis with a slot reinforced with fiber); experimental Group B (prosthesis with a slot filled with 3D-printed material), negative control Group C (prosthesis with a slot); and control Group D (full-contour prosthesis). Fracture strength exams were performed with a universal tester. The fracture patterns were examined. A statistical analysis was conducted using one-way ANOVA and Tukey HSD test., Results: The control group exhibited a significantly higher mean flexural load (D: 306.32 ± 50.76 N) compared to the other groups (A: 194.37 ± 68.02 N; B: 178.25 ± 42.67 N; and C: 156.68 ± 29.73 N; [P < .001]). No differences were identified among Groups A, B, and C. The fracture pattern differed between the nonreinforced Groups B, C, and D and reinforced Group A, with catastrophic failure observed in the nonreinforced group and unseparated failure observed in the reinforced group., Conclusions: The study findings demonstrate that the incorporation of Ribbond in 3D-printed, interim fixed dental prostheses does not significantly enhance their fracture strength. However, it does lead to a noticeable change in the fracture behavior, shifting from a complete failure to an incomplete fracture pattern.

Objectives: Dysregulation of lipid homeostasis pathway causes many liver diseases, including hepatic steatosis. One of the primary factors contributing to lipid accumulation is fatty acid uptake by the liver. Transmembrane protein 135 (TMEM135), which exists in mitochondria and peroxisomes, participates in intracellular lipid metabolism. This study aims to investigate the role of TMEM135 on regulating cellular lipid import in the liver., Methods: We used in vivo, ex vivo, and in vitro models of steatosis. TMEM135 knockout (TMEM135KO) and wild type (WT) mice were fed a high-fat diet (HFD) to induce hepatic steatosis. Primary mouse hepatocytes and AML12 cells were treated with free fatty acid (FFA). Additionally, TMEM135-deficient stable cells and overexpressed cells were established using AML12 cells., Results: TMEM135 deficiency mitigated lipid accumulation in the liver of HFD-fed TMEM135KO mice. TMEM135-depleted primary hepatocytes and AML12 cells exhibited less lipid accumulation when treated with FFA compared to control cells, as shown as lipid droplets. Consistently, the effect of TMEM135 depletion on lipid accumulation was completely reversed under TMEM135 overexpression conditions. CD36 expression was markedly induced by HFD or FFA, which was reduced by TMEM135 depletion. Among the SIRT family proteins, only SIRT1 expression definitely increased in the liver of HFD-fed TMEM135KO mice along with a significant increase in NAD + /NADH ratio. However, inhibition of SIRT1 in TMEM135-depleted cells using siSIRT1 or the SIRT1 inhibitor EX-527 resulted in an increase of CD36 expression and consequent TG levels., Conclusions: TMEM135 depletion attenuates CD36 expression in a SIRT1-dependent manner, thereby reducing cellular lipid uptake and hepatic steatosis., Competing Interests: Declaration of competing interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript., (Copyright © 2024. Published by Elsevier GmbH.)

The ability to tailor surface area, porosity, and morphologies has driven extensive research into the synthesis of metal-organic frameworks derived carbons and their applications in energy storage. This study presents the development of three-dimensional hierarchically porous carbon derived from polystyrene and small-sized zeolitic imidazolate framework-8 (ZIF-8) particles. Incorporating nanometer-sized ZIF-8 particles forms a core-shell structure in the pre-carbonization stage, transforming into a porous carbon material with a range of pores from micro to macropores after carbonization. The carbonized material's electrode demonstrates a high capacitance of 428.8 F g -1 at 1 mV s -1 in the three-electrode setup and a very high specific energy of 48.75 Wh kg -1 at 50 mA g -1 in the packed flat cell configuration. This exceptional electrochemical performance is attributed to the composite carbon material's high surface area, well-developed pore structure, and self-doped nitrogen content., (© 2024 Wiley-VCH GmbH.)

ETV2/ER71, an ETS (E-twenty six) transcription factor, is critical for hematopoiesis and vascular development. However, research about the molecular mechanisms behind ETV2-mediated gene transcription is limited. Herein, we demonstrate that ETV2 and KDM4A, an H3K9 demethylase, regulate hematopoietic and endothelial genes. Etv2 -/- mouse embryonic stem cells (mESCs), which fail to generate hematopoietic and endothelial cells, exhibit enhanced H3K9me3 levels in hematopoietic and endothelial genes. ETV2 interacts with KDM4A, and the ETV2-mediated transcriptional activation of hematopoietic and endothelial genes depends on KDM4A histone demethylase activity. The ETV2 and KDM4A complex binds to the transcription regulatory regions of genes directly regulated by ETV2. Mice lacking Kdm4a and Etv2 in endothelial cells ( Cdh5Cre:Kdm:Etv2 f/f mice) display a more severe perfusion recovery and neovascularization defect, compared with Cdh5Cre:Kdm4a f/f mice, Cdh5Cre:Etv2 f/f mice, and controls. Collectively, we demonstrate that ETV2 interacts with KDM4A, and that this interaction is critical for hematovascular lineage generation and vascular regeneration., Competing Interests: C.P. has a United States Patent (No. 10,023,842 B2. Title: Endothelial and endothelial-like cells produced from fibroblasts and uses related thereto), but the patent has nothing to do with the current manuscript., (© 2024 The Author(s).)

Renewable chemicals, which are made from renewable resources such as biomass, have attracted significant interest as substitutes for natural gas- or petroleum-derived chemicals to enhance the sustainability of the chemical and petrochemical industries. Polybutylene adipate terephthalate (PBAT), which is a copolyester of 1,4-butanediol (1,4-BDO), adipic acid (AA), and dimethyl terephthalate (DMT) or terephthalic acid (TPA), has garnered significant interest as a biodegradable polymer. This study assesses the non-biological production of PBAT monomers from biomass feedstocks via heterogeneous catalytic reactions. The biomass-based catalytic routes to each monomer are analyzed and compared to conventional routes. Although no fully commercialized catalytic processes for direct conversion of biomass into 1,4-BDO, AA, DMT, and TPA are available, emerging and promising catalytic routes have been proposed. The proposed biomass-based catalytic pathways toward 1,4-BDO, AA, DMT, and TPA are not yet fully competitive with conventional fossil fuel-based pathways mainly due to high feedstock prices and the existence of other alternatives. However, given continuous technological advances in the renewable production of PBAT monomers, bio-based PBAT should be economically viable in the near future., (© 2024 The Authors. ChemSusChem published by Wiley-VCH GmbH.)

Intratracheal instillation (ITI) is considered the most pragmatic approach for investigating the potential toxicities of various respiratory exposure materials. Various respiratory exposure materials, including nanomaterials, hazardous air pollutants, fine dust, and household biocides, have raised public health concerns because of limited toxicological information and increasing consumption. Hence, toxicity studies using ITI in laboratory animals are important to accurately assess the human risks associated with these respiratory-exposed materials. However, data to adequately support the study design of ITI toxicity studies, particularly those examining the effects of commonly used vehicles following repeated exposure are insufficient. Therefore, in this study, we examined the effects of 16 types of commonly used vehicles in toxicity studies following 14-day repeated ITI in mice. General health endpoints (mortality, clinical signs, and body weight) were monitored throughout the study period, and terminal endpoints (gross observation, lung weight, bronchoalveolar lavage fluid analysis, and lung histopathological examination) were assessed after terminal sacrifice. Saline and phosphate-buffered saline elicited the least response, whereas corn oil (50 µL) showed the most severe toxicity findings. In addition, several commonly used vehicles, including distilled water, sodium carboxymethyl cellulose, dimethyl sulfoxide, ethanol, Tween 20, and Tween 80, induced mild-to-severe toxicity in the respiratory system. Based on the results of this study, some commonly used vehicles in toxicity studies should be used with caution when the ITI exposure route is considered. These results provide important background information on the effects of vehicles in ITI toxicity studies along with valuable insights for designing toxicity studies using respiratory exposure materials., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)